Small molecule-mediated stabilization of vesicle-associated helical [alpha]-synuclein inhibits pathogenic misfolding and aggregation

• Published in: Nature communications 2014-12, Vol.5, p.5857
• Main Authors: Fonseca-ornelas, Luis, Eisbach, Sybille E, Paulat, Maria, Giller, Karin, Fernández, Claudio O, Outeiro, Tiago F, Becker, Stefan, Zweckstetter, Markus
• Format: Article
• Language: English
• ISSN: 2041-1723
• DOI: 10.1038/ncomms6857

α-synuclein is an abundant presynaptic protein that is important for regulation of synaptic vesicle trafficking, and whose misfolding plays a key role in Parkinson's disease. While α-synuclein is disordered in solution, it folds into a helical conformation when bound to synaptic vesicles. Stabilization of helical, folded α-synuclein might therefore interfere with α-synuclein-induced neurotoxicity. Here we show that several small molecules, which delay aggregation of α-synuclein in solution, including the Parkinson's disease drug selegiline, fail to interfere with misfolding of vesicle-bound α-synuclein. In contrast, the porphyrin phtalocyanine tetrasulfonate directly binds to vesicle-bound α-synuclein, stabilizes its helical conformation and thereby delays pathogenic misfolding and aggregation. Our study suggests that small-molecule-mediated stabilization of helical vesicle-bound α-synuclein opens new possibilities to target Parkinson's disease and related synucleinopathies.